The amino acids tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine (DOPA), tyrosine and phenylalanine are metabolically converted to tryptamine, 5-hydroxytryptamine, 3,4-dihydroxyphenethylamine or dopamine, tyramine and phenethylamino respectively by an aromatic amino acid decarboxylase. It is believed that the aromatic amino acid decarboxylase enzyme is non-specific, particularly, insofar as peripheral catalysis is concerned. Evidence does exist, however, to indicate that in the brain specific decarboxylation enzymes exist for each of DOPA and 5-hydroxytryptamine.
The above-enumerated aromatic amines are known to be involved in various pathophysiological processes. For example, it has been found that tryptamine, the decarboxylation product of tryptophan is enzymatically methylated to monomethyltryptamine which in turn is methylated enzymatically to dimethyltryptamine (DMT) in human red blood cells, plasma and platelets. The methylating enzyme is present in many mammalian species and has been shown to be produced in brain tissues of several species including man. DMT which has strong hallucinogenic or psychomimetic properties may play a role in the etiology of schizophrenia and other pyschotic disorders. Hence any agent which would block formation of DMT may be useful as an antipsychotic agent. Blocking the decarboxylation of tryptophan results in decreased levels of tryptamine, removing the substrate for DMT formation. Hence an inhibitor of aromatic amino acid decarboxylase which would block conversion of tryptophan to tryptamine may be useful as an antipsychotic agent.
Both 5-hydroxytryptamine (5-HT), the decarboxylation product of 5-hydroxytryptophan and 3,4-dihydroxyphenethylamine (dopamine) the decarboxylation product of DOPA are involved in peripheral and central physiological processes, and agents which are effective in the control of levels of these amines have resulted in useful pharmacological agents. It has been shown that central or brain levels of 5-HT and norepinephrine, which is formed metabolically by hydroxylation of dopamine, are higher in patients with manic disorders than in individuals without such disorders. It has also been shown that agents which decrease central levels of monoamines, for example, 5-HT and particularly norepinephrine have antimanic properties when given to human subjects, whereas drugs that increase monoamine levels could precipitate mania in susceptible individuals. Hence, agents which block formation of 5-HT and dopamine, such as, for example, by inhibiting the aromatic amino acid decarboxylation enzyme which converts 5-hydroxytryptophan and DOPA to 5-HT and dopamine respectively may be useful as antipsychotic agents or major tranquilizers in treating manic disorders.
It has also been shown that agents useful in inhibiting the decarboxylation of DOPA to dopamine are useful in the treatment of Parkinsonism when administered concurrently with exogenous DOPA or L-DOPA. It is believed that Parkinsonism is due, at least in part, to decreased central levels of dopamine since exogenous administration of DOPA or L-DOPA is known to be an effective means of treating Parkinsonism. However, since exogenously administered DOPA is readily converted enzymatically to dopamine peripherally it is necessary to administer large amounts in order to have increased absorption centrally. DOPA readily penetrates the blood-brain barrier whereas dopamine does not. Administration of DOPA or L-DOPA in conjunction with a peripherally active inhibitor of the enzyme which converts DOPA to dopamine reduces the amount of L-DOPA that must be administered in order to have adequate circulating levels for central absorption. Other advantages are also realized by administration of an aromatic amino acid decarboxylase inhibitor along with L-DOPA. By preventing formation of dopamine peripherally, side effects attributed to dopamine such as, cardiac arrhythmia, nausea and vomiting may be avoided.
Studies indicate that levels of 5-hydroxytryptamine (5-HT) are lower in patients with depressive syndromes than in individuals without such syndromes. Also, administration of exogenous L-5-hydroxytryptophan (L-5-HTP0 is effective in treating certain depressed patients. However, as with DOPA, since L-5-HTP is readily metabolized peripherally to 5-HT in order to achieve increased central levels of the amino acid. It has been shown that by administering an inhibitor of the aromatic amino acid decarboxylase enzyme that catalyzes the formation of 5-HT from 5-HT peripherally the amount of exogenous 5-HTP required to give increased central levels is markedly reduced. In other words inhibitors of aromatic amino acid decarboxylase when used in conjunction with exogenous 5-HTP have been shown to be useful in treating depression.
Agents which block peripheral conversion of 5-HTP to 5-HT may be useful in treating other conditions which respond to increased central levels of 5-HTP as a result of exogenous administration of 5-HTP. It has been shown that exogenous L-5-HTP is useful in treating action myoclonus. Also, studies reveal that administration of exogenous 5-HTP is useful in treating insomnia. Hence concurrent administration of 5-HTP and an aromatic amino acid decarboxylase inhibitor may be beneficial in treating these conditions.
Blocking peripheral formation of 5-hydroxytryptamine may result in other beneficial effects since it is known that 5-HT is involved, for example, in the etiology of rheumatoid arthritis and the carbinoid syndrome by increasing collagen levels. Also, it is reported that 5-HT is the primary autocoid responsible for anaphylactoid reactions in human subjects as well as bronchoconstriction in asthmatic human subjects, and agents which antagonize or inhibit formation of 5-HT are useful in treating these conditions. 5-HT is known to cause platelet aggregation and has been implicated as a causal factor in the post-gastrectomy dumping syndrome and migraine headache. Methylsergide, a 5-hydroxytryptamine antagonist, has proven effective in treating post-gastrectomy dumping syndrome.
It has been suggested that phenethylamine, the decarboxylation product of phenylalanine, as an endogenous compound contributes to schizophrenic symptoms and triggers migraine headaches. Also, it has been suggested that endogenous tyramine, the decarboxylation product of tyrosine, contributes to seizure disorders.
Hence, it is readily evident that agents which are useful in regulating the levels of aromatic amino acids and amines find use in many pharmacological situations. The compounds of the present invention are inhibitors of the aromatic amino acid decarboxylase which converts tryptophan, 5-hydroxytryptophan, 3,4-dihydroxyphenylalanine, tyrosine and phenylalanine to the respective amines and hence provide useful pharmacologic agents.